The Marburg and Ebola filoviruses have produced outbreaks of fatal hemorrhagic fever with mortality rates as high as 90%, yet there are still no effective means to protect human populations against these emerging virulent pathogens, raising serious concerns over their exploitation by terrorist groups. The lack of progress in producing effective vaccines and antiviral drugs for the treatment of filovirus infection can be traced to the stringent requirement for biosafety level 4 containment and (until recently) to the paucity of suitable systems for altering the filovirus genome at will. Thus, the research proposed here seeks to generate replication-incompetent virus-like particles (VLPs) for use as anti-Ebola virus vaccines and for establishing large-scale screening systems to identify potentially effective antiviral compounds. These aims are now feasible because of a reverse genetics system recently developed in the applicant's laboratory. In Aim 1, candidate VLPs will be tested for protective efficacy in mice given different routes of administration, before challenge with an otherwise lethal dose of wild-type Ebola Zaire virus. The four most promising vaccine protocols will then be evaluated in a primate model (cynomolgus macaques) to determine their potential efficacy in humans. Aim 2 will seek to generate and evaluate VLP-based systems to identify antivirals that block Ebola virus infection by interfering with viral entry, replication, assembly, or budding. This two-pronged research strategy represents a new and scientifically feasible initiative to lessen the threat of Ebola virus outbreaks, whether natural or introduced by bioterrorists.